Prognostic significance of extent of disease in bone in patients with androgen-independent prostate cancer.

PURPOSE: To evaluate the prognostic significance of a bone scan index (BSI) based on the weighted proportion of tumor involvement in individual bones, in relation to other factors and to survival in patients with androgen-independent prostate cancer. PATIENTS AND METHODS: Baseline radionuclide bone scans were reviewed in 191 assessable patients with androgen-independent disease who were enrolled onto an open, randomized trial of liarozole versus prednisone. The extent of skeletal involvement was assessed by scoring each scan using the BSI and independently according to the number of metastatic lesions. The relationship of the scored bone involvement to other known prognostic factors was explored in single- and multiple-variable analyses. RESULTS: In single-variable analyses, the pretreatment factors found to be associated with survival were age (P = .0446), performance status (P = .0005), baseline prostate-specific antigen (P = .0001), hemoglobin (P = .0001), alkaline phosphatase (P = .0002), AST (P = .0021), lactate dehydrogenase (P = .0001), and treatment (P = .0098). The extent of osseous disease was significant using both the BSI (P = .0001) and the number of lesions present (P = .0001). In multiple-variable proportional hazards analyses, only BSI, age, hemoglobin, lactate dehydrogenase, and treatment arm were associated with survival. When the patient population was divided into three equal groups, with BSI values of < 1.4%, 1.4% to 5.1%, and > 5.1%, median survivals of 18.3, 15.5, and 8.1 months, respectively, were observed (P = .0079). CONCLUSION: The BSI quantifies the extent of skeletal involvement by tumor. It allows the identification of patients with distinct prognoses for stratification in clinical trials. Further study is needed to assess the utility of serial BSI determinations in monitoring treatment effects. The BSI may be particularly useful in the evaluation of agents for which prostate-specific antigen changes do not reflect clinical outcomes accurately.

Diagnosing addictive disease in chronic pain patients.

As opiate therapy is increasingly accepted for the management of chronic pain, the consultation-liaison psychiatrist is often challenged to diagnose and provide treatment recommendations for addictive disease in chronic pain patients. Reviewed are the defining characteristics of addiction within the context of chronic pain, and the interesting commonalities between addictive disease and chronic pain. Guidelines for assessment of addiction in patients with chronic pain are presented, as are suggestions for the management of these concurrent disorders. Underlying this review is a belief that opiates should not be withheld from persons with chronic pain, even in the presence of addictive disease.

Bedside charting of pain levels in hospitalized patients with cancer: a randomized controlled trial.

Despite advances in the technology of cancer pain assessment and control, cancer pain often remains undertreated even in hospital settings. To determine whether a graphical display of cancer patients' pain levels might improve their treatment, the investigators conducted a randomized controlled trial. Patients assigned to the intervention group (N = 40) had periodic pain assessments by study staff, who graphically recorded their reported pain-intensity levels on bedside wall charts. Control group patients (N = 38) had periodic pain assessments by study staff but did not have this information displayed. The results failed to show a significant beneficial effect of the intervention on pain control, sleep, cancer-related symptoms, or analgesic dosing, but confidence intervals were broad. More research is needed to improve the quality of care for inpatients with cancer-related pain.

Beta-adrenergic receptors on human lymphocytes: comparison of down-regulation in vivo and in vitro.

beta-Adrenergic receptors on isolated human lymphocytes were enumerated using 125I-cyanopindolol (125I-CYP), after a 90-min exposure to 50 mumols/l l-isoproterenol in vitro. No change in receptor density could be shown in assays performed at 37 degrees C, although a 40% reduction was apparent in binding studies carried out at 4 degrees C. In contrast, beta-adrenergic receptors on lymphocytes from mild asthmatics after a 3-week course of oral terbutaline showed a 40% reduction in receptor density regardless of the assay temperature, in addition to a 2.5-fold reduction in the receptor affinity for isoproterenol. The data are consistent with reports that a fraction of receptors are sequestered during short-term exposure to agonists. Sequestered receptors may or may not be detected by radioligand binding assays depending on the ligand of choice, temperature of the binding assay and duration of prior exposure to the agonist. After extended exposure to an agonist in vivo, the number of surface receptors was reduced, and sequestered receptors were not present, presumably as a result of degradation.

Candida and AIDS: evidence for protective antibody.

Clinical observation and animal models of candidosis suggest that, although T lymphocytes are important in preventing superficial candidosis, defence against systemic candidosis depends upon humoral immunity. An antibody response to the immunodominant 47 kD antigen of Candida albicans is invariably associated with recovery. The presence of this antibody in patients with chronic mucocutaneous candidosis and the acquired immunodeficiency syndrome (AIDS) could account for the rarity of disseminated candidal infection in these conditions. Polyclonal B cell activation may be responsible for the frequency with which this antibody is produced in AIDS. Antibody to the 47 kD antigen could be useful in the treatment and prevention of systemic candidosis, though not in the superficial candidosis of AIDS.

Calcium dependence of beta-adrenoceptor mediated cyclic AMP accumulation in human lymphocytes.

In intact human lymphocytes, cyclic AMP accumulation in response to isoproterenol was inhibited by 5 mM EDTA, by deletion of calcium ions from the medium and by 1 mM lanthanum chloride, but not by 1 microM verapamil or by 10 microM nifedipine. A23187 caused a modest increase in cyclic AMP content. Exposure of lymphocytes to 5 microM 1-isoproterenol desensitized the cells to subsequent beta-adrenergic stimulation, reducing cyclic AMP accumulation. With higher concentrations of 1-isoproterenol (50 microM), receptor density was reduced as well. None of the above agents attenuated losses in agonist-stimulated cyclic AMP accumulation induced by treatment with 5 microM isoproterenol for 90 min. These data suggest that calcium ions, both those present in the extracellular medium and those bound to the plasma membrane, are required for isoproterenol-stimulation of adenylate cyclase. In addition, it appears that neither the presence of extracellular calcium ions nor full activation of adenylate cyclase are required for desensitization.

An inside look at the UCLA P&T committee: how does it influence prescribing practices?

In the first of a series of exclusive P & T interviews in Hospital Formulary, Dr. Matthew Conolly describes the operation of the UCLA P & T Committee. He stresses that the role of their Committee is to educate the hospital staff--not to police prescribing habits. In maintaining the formulary, the Committee uses several effective methods of staff education regarding drug use and cost containment, including the formulary itself, other pharmacy service publications, lectures, noontime conferences, and grand rounds. The process by which P & T decisions become policy at the UCLA Medical Center is outlined. Areas of controversy and challenge in maintaining a formulary in this changing health care environment are highlighted.

Rebound hyperresponsiveness to muscarinic stimulation after chronic therapy with an inhaled muscarinic antagonist.

In 9 young subjects with mild asthma, we investigated the possibility that chronic daily administration of an inhaled muscarinic antagonist (ipratropium bromide) might increase the response of muscarinic receptors in airway smooth muscle to agonist stimulation caused by receptor upregulation. Subjects inhaled 60 micrograms of ipratropium 4 times daily for 3 wk. Methacholine bronchoprovocation (with or without acute pretreatment with ipratropium) was performed before (control period) and during 3 wk of daily ipratropium therapy (medication period). At the end of the medication period, subjects returned at 12, 24, 48, and 72 h after the last dose of ipratropium (withdrawal period) to determine the provocative concentration of methacholine producing a 20% decrease in FEV1 (PC20). During the medication period, there was no significant diminution of the acute bronchodilator response to ipratropium or of the protective effect of ipratropium against methacholine-induced bronchospasm when compared with the control period. During the withdrawal period, mean in PC20 was significantly less (increased airway responsiveness) at 24 h than during the control period (p less than 0.01) and returned to the control period value within 48 to 72 h. We conclude that daily administration of ipratropium to mildly asthmatic subjects for 3 wk does not produce tolerance to either the bronchodilator effect of ipratropium or to its inhibition of methacholine-induced bronchospasm but does induce transient supersensitivity of airway cholinergic receptors to muscarinic stimulation.

The effects of some beta lactam antibiotics on (3H)-methyl-yohimbine binding to intact human platelets.

Several antibiotics have been reported to cause a bleeding diathesis in man, characterized by reduced platelet aggregation. We investigated the effects of several of the penicillins and of moxalactam on the binding of (3H)-methyl-yohimbine to intact human platelets. The (3H)-methyl-yohimbine binding met the criteria for interaction at an alpha2 adrenergic binding site and showed low interindividual variability. Penicillin G, ticarcillin, carbenicillin, piperacillin and moxalactam all inhibited (3H)-methyl-yohimbine binding, but at concentrations far in excess of clinically achievable plasma levels. We conclude that these compounds exert their antiplatelet effects by a mechanism other than competitive inhibition of catecholamine binding.

Orthostatic effect of imipramine and doxepin in depressed geriatric outpatients.

Blood pressure measurements were collected from 36 depressed geriatric outpatients (ages 55 to 81 years) enrolled in a double-blind, placebo-controlled study of the efficacy of doxepin and imipramine. Mean systolic postural changes were 25.9 mm Hg for imipramine, significantly higher than the 10.5 mm Hg for doxepin, and 12.4 mm Hg for placebo. The orthostatic drop in the imipramine group was only weakly related to dose and did not correlate with amount of pretreatment orthostatic hypotension or with duration of treatment. The increased orthostatic hypotension occurred early in treatment and at low doses of imipramine. Accordingly, caution is advised in the use of imipramine for the elderly.

Selective subsensitization of beta-adrenergic receptors in central airways of asthmatics and normal subjects during long-term therapy with inhaled salbutamol.

In five subjects with mild asthma and in five normal subjects, we determined the effect of a 4 wk course of inhaled salbutamol (albuterol), 200 micrograms q.i.d., on (1) acute bronchodilator responsiveness, (2) bronchial sensitivity to inhaled histamine, (3) beta-adrenergic protection against histamine-induced bronchospasm, and (4) beta-receptor density of peripheral blood lymphocytes. We observed a diminution in central airway bronchodilator responsiveness (as measured by airway conductance responses) to acutely inhaled salbutamol and to subcutaneous terbutaline in both groups of subjects, although only the response to subcutaneous terbutaline was statistically significant (p less than 0.02). On the other hand, no impairment of small airway bronchodilator responsiveness was noted in either group of subjects when responses were measured as partial expiratory flow rates at 60% below total lung capacity. These findings suggest the development of selective subsensitization of beta-receptors in the larger central airways, where a proportionately greater amount of the inhaled beta-agonist aerosol would necessarily be deposited. A greater loss of protection against histamine-induced bronchospasm was seen in asthmatics than in normals (approximately twofold), although the difference was not significant. A modest but not significant reduction in peripheral blood lymphocyte beta-receptor density was observed by the end of the 4 wk treatment period. The possibility that the observed changes in bronchodilator responsiveness might influence the morbidity and mortality associated with bronchial asthma is discussed.

Reversal of human lymphocyte beta-adrenoceptor desensitization by glucocorticoids.

To investigate the effect of glucocorticoids on beta-agonist-induced desensitization, we studied the effect of a single intravenous dose of methylprednisolone (2 mg/kg) on beta-receptor density and affinity in lymphocytes from four normal and four mildly asthmatic subjects at the end of 3 to 5 wk of terbutaline therapy and from four normal subjects taking no other drug. Terbutaline decreased (-)[3H]-dihydroalprenolol binding sites by 53% in normal and by 42% in asthmatic subjects. Methylprednisolone restored the number of binding sites to levels statistically indistinguishable from the preterbutaline values in both groups of subjects. In subjects not exposed to terbutaline beforehand there was no significant alteration in receptor density after methylprednisolone, nor in normal lymphocytes incubated in vitro for 90 min with hydrocortisone (10(-5)M). No significant change in the dissociation constant was observed in any situation. A single intravenous dose of methylprednisolone reverses terbutaline-induced down-regulation of beta-adrenoceptors. This may provide a mechanism for the beneficial effect of steroids in restoring catecholamine responsiveness in asthmatic subjects.

Lymphocyte beta-adrenergic receptors are not altered in hyperthyroidism.

Binding of (-)3H]-dihydroalprenolol (3H-DHA) to lymphocytes from five thyrotoxic patients and five age- and sex-matched contents were examined to ascertain whether beta-adrenergic receptor number or binding affinity were altered in thyrotoxicosis. Whereas an increase in beta-adrenoceptor density has been reported in triiodothyronine-induced hyperthyroidism, we did not find changes in beta-adrenergic receptor density or binding affinity. In one patient studied sequentially, we did not find alteration in 3H-DHA bindings before or after the subject was rendered euthyroid. We conclude that lymphocyte beta-adrenergic receptor density and affinity are not altered in spontaneous hyperthyroidism.

Subsensitization of beta-adrenoceptors in airways and lymphocytes of healthy and asthmatic subjects.

Subsensitization of beta-adrenoceptors in airways and lymphocytes developing during 4 to 5 wk of orally administered terbutaline (a long-acting beta 2 selective bronchodilator) was compared in 10 healthy subjects and 11 subjects with mild asthma. The following results were obtained. Normal subjects developed a significant reduction in acute bronchodilator responsiveness to inhaled isoproterenol but not to subcutaneously administered terbutaline. The subjects with asthma failed to develop any alteration in responsiveness to either inhaled isoproterenol or subcutaneously administered terbutaline. None of 5 normal or 4 asthmatic subjects studied demonstrated any significant change in sensitivity to histamine-induced bronchospasm or any significant decrease in the acute protective effect of subcutaneously administered terbutaline against histamine-induced bronchospasm. Marked and significant decreases occurred in the density of lymphocyte beta-receptor sites in both groups. Maximal isoproterenol-stimulated cyclic AMP responses in lymphocytes from normal subjects were reduced, but in asthmatics, in whom the baseline values were lower to begin with, a similar decrease was not observed. In most instances, the number of receptor sites returned to normal within 2 wk after cessation of terbutaline. A single dose of methylprednisolone caused a return to normal values within 16 h. We conclude that chronic therapy with an oral beta 2-adrenostimulant, although producing striking and significant down-regulation of beta-adrenergic receptors of peripheral lymphocytes, does not lead to physiologically detectable beta-adrenoceptor subsensitivity in the airways of asthmatics or to consistent subsensitivity in the airways of healthy persons.